A Swiss team has designed a “better” ADC by using synthetic DNA strands in a system that more precisely recognizes and delivers its payload to cancer cells. Their paper appears in the latest issue of Nature Biotechnology. ADCs (antibody–drug conjugates) are one of the most promising new classes of cancer drugs, with a market valued at approximately $12 billion.
The team behind this work is from the University of Geneva (UNIGE) and the senior author is Nicolas Winssinger, PhD, professor in the department of organic chemistry of the School of Chemistry and Biochemistry, Faculty of Science.
“While ADCs are exceptionally effective compared to standard of care, their penetration of solid tumors is hampered by the size of the monoclonal antibodies [approximately 150 kDa]. Another limitation is the payload size,” Winssinger told Inside Precision Medicine.
The new approach uses affibodies, which are <10 kDa. He added that their system “provides an amplification of the payload delivery (over 100 drug per antigen binding event) yet, all components used are significantly smaller in size than a monoclonal antibody. It also lends itself to the delivery of drug combinations.”
Sixteen ADCs are approved in the U.S. for cancer treatment. Enhertu, which targets HER-2 positive tumors, is one of the most successful examples. It was developed by AstraZeneca and Daiichi Sankyo.
The question of how cancer cells can be targeted without damaging healthy tissue is one of the major challenges in oncology. ADCs use monoclonal antibodies to deliver therapeutic agents directly to specific cancer cells. But since their poor penetration into tumor tissue and restricted capacity for carrying drug payloads has restricted their application, this team looked for another approach.
The UNIGE researchers system’s smaller DNA components can move through tumors more easily than traditional antibody-based therapies. The DNA strands can each carry distinct components, including two different cancer-targeting binders and a cytotoxic drug.
When two specific cancer markers bind to their respective DNA-linked binders, the components self-assemble precisely at the tumor site. This assembly delivers higher drug concentrations, amplified by multiple DNA fragments snapping together where needed. This process only occurs when both cancer markers are present. If either marker is missing, the hybridization chain reaction cannot initiate, and the drug remains inactive.
In laboratory studies, the technology successfully identified cancer cells with specific combinations of surface proteins and selectively delivered potent drugs—while nearby healthy cells remained unharmed. The researchers also demonstrated that multiple therapeutics can be combined within the same treatment, a strategy that may help prevent or overcome drug resistance.
“This could mark an important step forward in the evolution of medicine, with the introduction of a self-operating drug system. Until now, computers and AI have helped us design new drugs. What’s new here is that the drug itself can, in a simple way, ‘compute’ and respond intelligently to biological signals,” said Winssinger,
Speaking of their next steps, Winssinger said, “A key limitation of the current study is that it was performed with unmodified DNAs, which are metabolically labile. One possible solution would be to use mirror-image DNA. Another would be to use a synthetic DNA analog with optimized metabolic properties and pharmacological inertness. An important question for the field interfacing circuitry with pharmacology is to identify the most suitable oligonucleotide chemistry.
He added, “We have previously shown that peptide nucleic acid, a synthetic DNA mimic, is a possible contender, and we are currently exploring its performance in this context. Other important objectives are to expand the number of biomarkers that can be used to trigger the circuitry and to extend the range of outputs beyond small-molecule delivery.”
